crossing96/oncoscreening huggingface dataset:
Leflunomide Inhibits Proliferation and Induces Apoptosis via Suppressing Autophagy and PI3K/Akt Signaling Pathway in Human Bladder Cancer Cells.	INTRODUCTION: Bladder cancer is a lethal human malignancy. Currently, treatment for bladder cancer is limited. The anti-tumor effects of leflunomide have attracted much more concern in multiple human cancers. MATERIALS AND METHODS: This study evaluated the anti-tumor effects of leflunomide on cell viability, colony formation, apoptosis, and cell cycle in two human bladder carcinoma cell lines, 5637 and T24. Meanwhile, the underlying mechanism including PI3K/Akt signaling pathway and autophagy modulation was also identified. RESULTS: Leflunomide markedly inhibited the growth of both bladder cancer cell lines and induced apoptosis and cell cycle arrest in S phase. The phosphorylation levels of Akt and P70S6K in both cell lines were significantly down-regulated with leflunomide treatment. Furthermore, the deceased formation of autophagosomes and the accumulation of LC3II and P62 suggested the blockade of autophagy by leflunomide. Modulation of autophagy with rapamycin and chloroquine markedly attenuated and enhanced the cytostatic effects of leflunomide, respectively. CONCLUSION: Leflunomide significantly reduced the cell viability of bladder cancer cells via inducing apoptosis and cell cycle arrest and suppressing the PI3K/Akt signaling pathway. In addition, the blockade of autophagy was observed, and autophagy inhibition enhanced leflunomide-mediating anti-tumor effects. Our data presented here offer novel ideas for comprehensive therapeutic regimes on bladder cancer.	bladder
Upper urinary tract urothelial carcinomas - our experience.	INTRODUCTION: Urothelial carcinoma is the second most common urological malignancy. Around 5-10% of tumors are found in the upper urinary tract, while almost 90-95% are in the bladder. METHODS: Patients of our department diagnosed with upper urinary tract urothelial carcinoma (UTUC) during the period 2014-2018 were included. The frequency, selected therapeutic procedures and treatment results were analyzed. RESULTS: In the last 5 years, 21 patients with UTUC were diagnosed and surgically treated at the Department of Urology, Regional Hospital Nachod. The main surgical approach was nephroureterectomy. Mortality was 28.6% due to the original tumor diagnosis. Urothelial carcinoma of the upper urinary tract was more common in men than in women in our patient group. CONCLUSION: Unfortunately, urothelial carcinomas of the upper urinary tract are often dealt with only in locally advanced stages or when nodal or distant metastases are present, making any possible administration of adjuvant chemotherapy complicated as it fails to provide a sufficient effect. Therefore, radical nephroureterectomy remains the gold standard for more than a half of patients. Overall survival depends largely on the presence of distant metastases. The pT category is the major influencing parameter for a relapse.	bladder
Validation of a Questionnaire-Suitable Comorbidity Index in Patients Undergoing Radical Cystectomy.	OBJECTIVE: To investigate the capability of a modified self-administrable comorbidity index recommended in the standard sets for neoplastic diseases published by the International Consortium for Health Outcomes Measurement (ICHOM) to predict 90-day and long-term mortality after radical cystectomy. METHODS: A single-center series of 1,337 consecutive patients who underwent radical cystectomy for muscle-invasive or high-risk non-muscle-invasive urothelial or undifferentiated bladder cancer were stratified by the modified self-administrable comorbidity index and Charlson score, respectively. Multivariate logit models (for 90-day mortality) and proportional-hazards models (for overall and non-bladder cancer mortality) were used for statistical workup. RESULTS: Considering 90-day mortality, both comorbidity indexes contributed independent information when analyzed together with age (p < 0.0001). The Charlson score performed slightly better (area under the curve [AUC] 0.74 vs. 0.72 for the ICHOM-recommended comorbidity index). Considering 5-year overall mortality in 727 patients with complete observation, the performance of both measures was similar (AUC 0.63 vs. 0.62, including age AUC 0.66 for both indexes). With 6-sided stratifications, the modified self-administrable comorbidity index separated the risk groups slightly better (p values for directly neighboring curves: 0.0068-0.1043 vs. 0.0001-0.8100). CONCLUSION: The ICHOM-recommended modified self-administrable comorbidity index is capable of predicting 90-day mortality and long-term non-bladder cancer mortality after radical cystectomy similarly to the commonly used Charlson score.	bladder
Stromal LAG-3(+) cells infiltration defines poor prognosis subtype muscle-invasive bladder cancer with immunoevasive contexture.	BACKGROUND: Lymphocyte activation gene 3 (LAG-3) is a promising immune checkpoint therapeutic target being evaluated in clinical trials. We assessed the LAG-3(+) cells distribution, its association with clinical outcomes and immune contexture and its role in the landscape of muscle-invasive bladder cancer (MIBC) treatment. METHODS: 141 patients with MIBC from Zhongshan Hospital were included for survival and adjuvant chemotherapy (ACT) benefit analyses. 32 fresh resected samples of MIBC were collected to detect CD8(+) T cells functional state. The molecular classification analyses were based on 391 patients with MIBC from The Cancer Genome Atlas. Immunohistochemistry and flow cytometry were performed to characterize various immune cells infiltration. RESULTS: In Kaplan-Meier analyses and Cox regression models, stromal LAG-3(+) cells enrichment was consistently associated with inferior overall survival and disease-free survival, and indicated suboptimal responsiveness to ACT. Patents with high stromal LAG-3(+) cells possessed increased protumor cells, immunosuppressive cytokines and immune checkpoint expression. The phenotypic analyses of CD8(+) T cells correlated its dysfunctional state with LAG-3(+) cells. Besides, LAG-3 mRNA level was linked to luminal and basal subtypes of MIBC. LAG-3-high tumors exhibited limited FGFR3 mutation and signaling signature, and displayed activated immunotherapeutic and EGFR-associated pathway. CONCLUSIONS: Stromal LAG-3(+) cells abundance indicated an immunoevasive contexture with dysfunctional CD8(+) T cells, and represented an independent predictor for adverse survival outcome and ACT resistance in MIBC. LAG-3 expression could potentially be a novel biomarker for FGFR3-targeted and EGFR-targeted therapies and immunotherapy. The crucial role of LAG-3(+) cells in the therapeutic landscape of MIBC needs further validation retrospectively and prospectively.	bladder
Effects of Arsenic (+3 Oxidation State) Methyltransferase Gene Polymorphisms and Expression on Bladder Cancer: Evidence from a Systematic Review, Meta-analysis and TCGA Dataset.	Inorganic arsenic (iAs) is a recognized environment-related factor for bladder cancer (BCa). Arsenic (+3 oxidation state) methyltransferase (AS3MT) gene might influence BCa by regulating iAs metabolism. The aim of the present study was to explore whether AS3MT polymorphisms could affect BCa susceptibility. We systematically reviewed eligible case-control studies about AS3MT polymorphisms and BCa and to further compare the genotype distribution and allele distribution between BCa patients and controls by meta-analysis for humans. Besides, to clarify the effects of AS3MT expression on BCa clinical outcomes and survival time, we also conducted a series of analyses based on The Cancer Genome Atlas dataset. Databases were systematically retrieved and we applied Stata software to perform meta-analysis. The registration of this study protocol is at PROSPERO and ID is CRD42019133947. Five articles were recruited and pooled results demonstrated that rs3740393 and rs11191438 polymorphisms were related to BCa risk in overall population (p < .05) in the overall population. In addition, GG and GC genotypes in rs3740393 and GG genotype in rs11191438 might be the susceptibility genotypes for BCa. Results based on 168 BCa samples from TGCA indicated that patients with higher expression of AS3MT had poor overall survival time and AS3MT expression is an independent indicator for BCa survival. This study identified that AS3MT polymorphisms could affect BCa risk and AS3MT expression was pivotal in prognosis of BCa.	bladder
Chemotherapy-Induced IL8 Upregulates MDR1/ABCB1 in Tumor Blood Vessels and Results in Unfavorable Outcome.	Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. SIGNIFICANCE: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.	bladder
Aberrantly glycosylated integrin α3β1 is a unique urinary biomarker for the diagnosis of bladder cancer.	Bladder cancer (BC) is the most common malignancy of the urinary tract. We developed a new and ELISA kit for detecting aberrantly glycosylated integrin α3β1 (AG31) in human urine. We analysed urine samples (n=408) of patients with BC, renal cell carcinoma (RCC), prostate cancer (PC), cystitis, nephritis, and prostatitis from two centres in China. The subjects in the validation groups (n=2317) were recruited from other centres in China between July 2012 and September 2013. Receiver operating characteristic (ROC) curves were used to determine diagnostic accuracy. AG31 levels in urine samples were significantly higher in patients with BC than in any of the control subjects. Moreover, elevated levels of AG31 in urine could distinguish BC from benign inflammatory diseases. Finally, the urinary AG31 test was much more sensitive and specific than the NMP22 test. Therefore, the urinary AG31 test will provide an ideal and assay for the detection of BCs.	bladder
Stratification of Intermediate-risk Non-muscle-invasive Bladder Cancer Patients: Implications for Adjuvant Therapies.	BACKGROUND: There is an urgent need to provide a risk-stratification tool for intermediate-risk non-muscle-invasive bladder cancer (NMIBC), especially at the time of bacillus Calmette-Guerin (BCG) shortage. OBJECTIVE: To assess whether patients with intermediate-risk NMIBC can be stratified into different risk groups, thereby providing a practical tool for the selection of the optimal adjuvant therapy, based on the individualized risk of disease progression. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of 636 patients with intermediate-risk NMIBC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A multivariable Cox-regression model was built to evaluate the impact of each variable on recurrence and progression to muscle-invasive disease. A Cox-based nomogram to predict patient-specific probability of disease progression was performed, and the decision curve analysis (DCA) was used to evaluate its clinical benefit. RESULTS AND LIMITATIONS: Within a median follow-up of 92 mo (interquartile range 56-118), disease recurrence and progression occurred in 346 (54%) and 91 (14%) patients, respectively. On multivariable analysis, age, early recurrence (<12 mo), and tumor size≥3cm were found to be independent predictors of progression. The Harrell C-index of the model for the prediction of progression was 0.75 and exceeded that of the model proposed by the International Bladder Consultation Group. DCA showed superior net benefits for the nomogram compared with the strategies of treating all/none and previous predictive models. Limitations are inherent to the retrospective design. CONCLUSIONS: We provided a risk-stratification tool that helps identify individual risk of disease progression in patients with intermediate-risk NMIBC. This tool outperforms standard strategies in the threshold probability range of interest and could help select the optimal intravesical therapy regimen based on the individual risk of disease progression. PATIENT SUMMARY: In this study, we provided a practical tool for risk stratification in patients with intermediate-risk non-muscle-invasive bladder cancer. This tool may help select the most appropriate adjuvant therapy (either bacillus Calmette-Guerin [BCG] or chemotherapy) based on patient and tumor characteristics, thus making a step forward toward the era of personalized medicine.	bladder
Monitoring of urothelial cancer disease status after treatment by digital droplet PCR liquid biopsy assays.	OBJECTIVES: Real-time monitoring of disease status would be beneficial for timely decision making in the treatment of urothelial cancer (UC), and may accelerate the evaluation of clinical trials. Use of cell free tumor DNA (cftDNA) as a biomarker in liquid biopsy is minimally invasive and its successful use has been reported in various cancer types, including UC. The objective of this study was to evaluate the use of digital droplet PCR (ddPCR)-based assays to monitor UC after treatment. METHOD AND MATERIALS: Blood, urine and matching formalin fixed, paraffin embedded diagnostic specimens were collected from 20 patients diagnosed with stage T1 (n = 2) and T2/T3 (n = 18) disease. SNaPshot assays, Sanger sequencing and whole exome sequencing were used to identify tumor-specific mutations, and somatic mutation status was confirmed using patient-matched DNAs extracted from buffy coats and peripheral blood mononucleocytes. The ddPCR assays of the tumor-specific mutations were used to detect the fractional abundance of cftDNA in plasma and urine. RESULTS: SNaPshot and Sanger sequencing identified point mutations in 70% of the patients that were assayable by ddPCR. Cases of remission and relapse monitored by assays for PIK3CA E542K and TP53 Y163C mutations in plasma and urine concurred with clinical observations up to 48 months from the start of chemotherapy. A new ddPCR assay for the telomerase reverse transcriptase (TERT) promoter (-124) mutation was developed. The TERT assay was able to detect mutations in cases below the limit of detection by SNaPshot. Whole exome sequencing identified a novel mutation, CNTNAP4 G727*. A ddPCR assay designed to detect this mutation was able to distinguish mutant from wild-type alleles. CONCLUSIONS: The study demonstrated that ddPCR assays could be used to detect cftDNA in liquid biopsy monitoring of the post-therapy disease status in patients with UC. Overall, 70% of the patients in our study harbored mutations that were assayable by ddPCR.	bladder
MiR-486-5p enhances cisplatin sensitivity of human muscle-invasive bladder cancer cells by induction of apoptosis and down-regulation of metastatic genes.	OBJECTIVES: Cisplatin is one of the common chemotherapy drugs for bladder cancer, and resistance to this drug is one of the major obstacles to effective chemotherapy. MicroRNAs (miRNAs) are a category of small noncoding RNAs that can regulate the expression of numerous genes. Recent studies showed that miRNAs can act as a powerful regulator of chemo-sensitivity in cancer cells. Hence, this study aimed to investigate the effects of miRNA-486-5p on cisplatin-sensitivity of different bladder cancer cells. MATERIAL AND METHODS: The 5637 and EJ138 cancer cells were treated with miRNA-486-5p and cisplatin, individually or in combination. RESULTS: Afterward, the cytotoxicity effects of these treatments were determined by MTT assay and the increased cisplatin-sensitivity observed in both cell lines, especially, 5637 cells. Moreover, subG1 phase cell cycle arrest, changes in the expression of caspase-9, caspase-3, P53, SIRT1, OLFM4, SMAD2, and Bcl-2 genes and nuclear fragmentation also revealed the induction of apoptosis in all treatments, which increased in combination groups. Also, the combination of miRNA-486-5p with cisplatin significantly down-regulated the expression of migration associated genes including ROCK, CD44, and MMP-9 as compared with cisplatin alone. CONCLUSION: Altogether, these results indicated that the miRNA-486-5p could induce apoptosis and inhibit cell migration ability of the cells. It seems that pre-electroporation of cells with miRNA-486-5p has useful results in the enhancement of cisplatin sensitivity of 5637 and EJ138 cancer cells and this combination may be a promising treatment strategy for bladder cancer therapy.	bladder
Anticancer effects of Mahanimbine alkaloid on the human bladder cancer cells are due to the induction of G0/G1 cell cycle arrest, apoptosis and autophagy.	PURPOSE: The main purpose of the current research work was to investigate the anticancer effects of Mahanimbine alkaloid in human bladder cancer cells along with examining its effects on cellular apoptosis, cell cycle phase distribution, and cell autophagy. METHODS: Cell viability was examined by WST-1 cell viability assay. Mahanimbine-induced apoptosis was examined by fluorescent microscopy using acridine orange (AO)/ethidium bromide (EB) staining as well as using flow cytometry in combination with annexin-v/propidium iodide (PI) staining. Further, western blot assay was used to study the effects of Mahanimbine on apoptosis-related protein expressions including Bax and Bcl-2. Autophagy induction was evaluated by transmission electron microscopy (TEM) and western blot. Flow cytometry was used to study the effects on cell cycle. RESULTS: The results showed that Mahanimbine decreased the viability of the human bladder cancer cells and exhibited an IC50 of 32.5 µM. The test molecule also caused remarkable changes in the morphology of human bladder cancer cells and inhibited their colony forming potential. The AO/EB staining assay showed that Mahanimbine inhibits the viability of cancer cells via induction of apoptotic cell death which was associated with increase in Bax and decrease in Bcl-2 levels. The apoptotic cells increased from 5.2% in control to around 75% at 100 µM concentration. Mahanimbine also led to dose-dependent G0/G1 cell cycle arrest. Autophagic vacuoles appeared in the treated cells indicating autophagic induction by the test molecule. The Mahanimbine-triggered autophagy was also linked with increase in the expression of LC3II and decrease in p62 expression. However, no apparent effects were observed on the LC3 I expression. CONCLUSION: Taken together, the results of this study indicate that Mahanimbine natural product has the potential to be developed as a promising anticancer agent against human bladder carcinoma but further studies are needed to this direction.	bladder
Molecular Genetic Features of Primary Nonurachal Enteric-type Adenocarcinoma, Urachal Adenocarcinoma, Mucinous Adenocarcinoma, and Intestinal Metaplasia/Adenoma: Review of the Literature and Next-generation Sequencing Study.	The diagnosis of primary adenocarcinoma of the urinary bladder may be challenging in routine practice. These tumors may morphologically and immunohistochemically overlap with urachal adenocarcinoma and colorectal adenocarcinoma. Further, their genetic background is poorly understood. We systematically searched the PubMed database for results of complex genetic evaluation of primary bladder adenocarcinoma subtypes. Subsequently, we designed our own series of bladder lesions. We evaluated 36 cases: 16 primary enteric-type adenocarcinomas, 7 urachal enteric adenocarcinomas, 3 primary mucinous/colloid adenocarcinomas, and 10 intestinal-type metaplasia/villous adenoma. Detailed clinical data were collected, and all cases were examined using targeted next-generation sequencing. On the basis of the literature, the first mutated gene in these tumors was reported to be KRAS in 11.3% of cases, followed by TERT promoter mutations in 28.5%. In addition to KRAS and TERT, other genes were also found to be frequently mutated in primary bladder adenocarcinoma, including TP53, PIK3CA, CTNNB1, APC, FBXW7, IDH2, and RB1. In our series, the most frequent gene mutations in primary enteric-type adenocarcinomas were as follows: TP53 (56%); BRCA2, KMT2B (both 33%); NOTCH2, KDR, ARID1B, POLE, PTEN, KRAS (all 28%); in urachal enteric adenocarcinoma they were as follows: TP53 (86%); PTEN, NOTCH (both 43%); in primary mucinous/colloid adenocarcinomas they were as follows: KRAS, GRIN2A, AURKB (all 67%); and, in intestinal-type metaplasia/villous adenoma, they were as follows: APC, PRKDC (both 60%); ROS1, ATM, KMT2D (all 50%). No specific mutational pattern was identified using cluster analysis for any of the groups. Herein, we describe the pathologic features and immunohistochemical staining patterns traditionally used in the differential diagnoses of glandular lesions of the bladder in routine surgical pathology. We outline the mutational landscape of these lesions as an aggregate of published data with additional data from our cohort. Although diagnostically not discriminatory, we document that the most common genetic alterations shared between these glandular neoplasms include TP53, APC (in the Wnt pathway), and KRAS (in the MAPK pathway) mutations.	bladder